DESCRIPTION: (Applicant's Abstract) Neuronal mechanisms that underlie cognitive processing are likely to involve modulation of synaptic function. Neuronal acetylcholine receptors (nAChRs) form a diverse group of channels that have been implicated in higher brain functions such as selective attention and learning and memory. Because, in particular, nAChRs are differentially permeable to the intracellular signal Ca2+, these receptors are ideally suited to contribute to a variety of long-lasting cellular events. In order to understand the role of nAChRs it is essential to understand their molecular properties. The goals of this proposal are to gain insight into: The synaptic functions of CNS nAChRs in terms of receptor composition and regulation. These aims will be addressed by testing two specific hypotheses: 1. Select nAChR subtypes serve dominant functions within CNS nuclei We suggest that the large number of nAChR subunits exist, not to form a vast number of nAChR subtypes, but to create a basic set of receptors, each of which has a minimal essential core of subunits. Inclusion of additional subunits would serve to modify their basic function. Thus we would predict that in areas of the brain where a large variety of nAChR subunits exist, certain types would dominate. 2. The level of intracellular Ca2+ controls the sensitivity of neuronal nAChRs We suggest that the function of one subtype of nAChR is to sense to the level of intracellular Ca2+ by adjusting its responsiveness to its transmitter. Thus, its function may be enhanced in the presence of ongoing synaptic activity. In turn, because nAChRs allow Ca2+ into cells they will contribute dynamically to intracellular Ca2+ signaling. Provided that this positive-feedback is kept regulated, nAChRs could contribute to long-lasting changes at synapses. If however, this process becomes unregulated, increased Ca2+ flux through potentiated nAChR channels could lead towards cell damage. By addressing these hypotheses, we will be able to offer neuronal mechanisms that could underlie higher brain functions and may help explain cholinergic-nicotinic dysfunction in certain diseases.